Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches.

Osteoporosis is a skeletal disorder characterized by bone loss, which results in architectural deterioration of the skeleton, compromised bone strength and an increased risk of fragility fractures. Most current therapies for osteoporosis stabilize the skeleton by inhibiting bone resorption (antiresorptive agents), but the development of anabolic therapies that can increase bone formation and bone mass is of great interest. Wnt signalling induces differentiation of bone-forming cells (osteoblasts) and suppresses the development of bone-resorbing cells (osteoclasts). The Wnt pathway is controlled by antagonists that interact either directly with Wnt proteins or with Wnt co-receptors. The importance of Wnt signalling in bone formation is indicated by skeletal disorders such as sclerosteosis and van Buchem syndrome, which are caused by mutations in the gene encoding the Wnt antagonist sclerostin (SOST). Experiments in mice have shown that downregulation or neutralization of Wnt antagonists enhances bone formation. Phase II clinical trials show that 1-year treatment with antisclerostin antibodies increases bone formation, decreases bone resorption and leads to a substantial increase in BMD. Consequently, Wnt signalling can be targeted by the neutralization of its extracellular antagonists to obtain a skeletal anabolic response.